Voriconazole (VRC, UK109496) is a novel antifungal agent synthesized by Pfizer Inc. USA on the basis of fluconazole, and is mainly used for patients with progressive, life-threatening immune damages. The market prospects of Voriconazole are broad because of its broad spectrum of antifungal activity, strong antibacterial efficacy and good safety, and because of the fast-growing demand for antifungal drugs in the domestic market.
The chemical name of Voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is represented by formula I:

The chemical name of Voriconazole condensation compound, an important intermediate, is (2R,3S/2S,3R)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is represented by formula II:

At present, the main synthesis method of the intermediate of formula II is shown in reaction scheme 1, comprising reacting 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone of formula III with 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine of formula IV, in the presence of metal zinc, iodine or Lewis acid, and an aprotic organic solvent, with or without lead. The mechanism is that zinc powder first reacts with the compound of formula IV to form an organozinc reagent, which then reacts with the compound of formula III. The compounds of formula III and IV can be prepared using commercially available starting materials or methods disclosed in the prior art.

However, zinc powder is easily oxidized after contacting with air. This leads to a problem of initiation and activation during the preparation of the zinc reagent. Previous zinc powder-activating technology mainly involved lead powder. However, lead is a metal element with highly toxic and is strictly controlled in pharmaceutical process, and thus is unfavorable for large-scale industrial production. In addition, the charging mode has a great influence on the reaction during the synthesis of Voriconazole condensation compound. An improper charging mode method will lead to increased content of impurity A in the reaction and further affect the impurity removal of post-treatment and subsequent hydrogenation, which is extremely unfavorable for the reaction. Thus, it is important to strictly control charging mode for the reaction. The chemical name of impurity A is 3-(6-(1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl)-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is represented by formula V:
